Asthma is a chronic respiratory disease of global importance. Mouse models of allergic asthma have been instrumental in advancing research and novel therapeutic strategies for patients. The ...application of relevant allergens and physiological routes of exposure in such models has led to valuable insights into the complexities of asthma onset and development as well as key disease mechanisms. Furthermore, environmental microbial exposures and infections have been shown to play a fundamental part in asthma pathogenesis and alter disease outcome. In this review, we delve into physiological mouse models of allergic asthma and explore literature reports on most significant interplays between microbial infections and asthma development with relevance to human disease.
Environmental microbial triggers shape the development and functionality of the immune system. Alveolar macrophages (AMs), tissue-resident macrophages of the lungs, are in constant and direct contact ...with inhaled particles and microbes. Such exposures likely impact AM reactivity to subsequent challenges by immunological imprinting mechanisms referred to as trained immunity. Here, we investigated whether a ubiquitous microbial compound has the potential to induce AM training in vivo. We discovered that intranasal exposure to ambient amounts of lipopolysaccharide (LPS) induced a pronounced AM memory response, characterized by enhanced reactivity upon pneumococcal challenge. Exploring the mechanistic basis of AM training, we identified a critical role of type 1 interferon signaling and found that inhibition of fatty acid oxidation and glutaminolysis significantly attenuated the training effect. Notably, adoptive transfer of trained AMs resulted in increased bacterial loads and tissue damage upon subsequent pneumococcal infection. In contrast, intranasal pre-exposure to LPS promoted bacterial clearance, highlighting the complexity of stimulus-induced immune responses, which likely involve multiple cell types and may depend on the local immunological and metabolic environment. Collectively, our findings demonstrate the profound impact of ambient microbial exposure on pulmonary immune memory and reveal tissue-specific features of trained immunity.
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Allergies are considered to represent mal-directed type 2 immune responses against mostly innocuous exogenous compounds. Immunoglobulin E (IgE) antibodies are a characteristic feature of allergies ...and mediate hypersensitivity against allergens through activation of effector cells, particularly mast cells (MCs). Although the physiological functions of this dangerous branch of immunity have remained enigmatic, recent evidence shows that allergic immune reactions can help to protect against the toxicity of venoms. Because bacteria are a potent alternative source of toxins, we assessed the possible role of allergy-like type 2 immunity in antibacterial host defense. We discovered that the adaptive immune response against Staphylococcus aureus (SA) skin infection substantially improved systemic host defense against secondary SA infections in mice. Moreover, this acquired protection depended on IgE effector mechanisms and MCs. Importantly, our results reveal a previously unknown physiological function of allergic immune responses, IgE antibodies, and MCs in host defense against a pathogenic bacterium.
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•Staphylococcus aureus skin infection leads to specific and functional IgE antibodies•Skin-initiated immunity protects against secondary lung and skin infections•Mast cells and IgE antibodies play key roles in acquired resistance to S. aureus•IgE-activated mast cells interfere with S. aureus growth and toxicity
The biological functions of IgE antibodies and mast cells, critical components of allergic diseases, have been enigmatic. Starkl et al. report a role of this allergy module of immunity in host defense against the bacterial pathogen Staphylococcus aureus.
SummaryAllergies are considered to represent mal-directed type 2 immune responses against mostly innocuous exogenous compounds. Immunoglobulin E (IgE) antibodies are a characteristic feature of ...allergies and mediate hypersensitivity against allergens through activation of effector cells, particularly mast cells (MCs). Although the physiological functions of this dangerous branch of immunity have remained enigmatic, recent evidence shows that allergic immune reactions can help to protect against the toxicity of venoms. Because bacteria are a potent alternative source of toxins, we assessed the possible role of allergy-like type 2 immunity in antibacterial host defense. We discovered that the adaptive immune response against Staphylococcus aureus (SA) skin infection substantially improved systemic host defense against secondary SA infections in mice. Moreover, this acquired protection depended on IgE effector mechanisms and MCs. Importantly, our results reveal a previously unknown physiological function of allergic immune responses, IgE antibodies, and MCs in host defense against a pathogenic bacterium.
Allergies are considered to represent mal-directed type 2 immune responses against mostly innocuous exogenous compounds. Immunoglobulin E (IgE) antibodies are a characteristic feature of allergies ...and mediate hypersensitivity against allergens through activation of effector cells, particularly mast cells (MCs). While any physiologic functions of this dangerous branch of immunity have remained enigmatic, recent evidence shows that allergic immune reactions can help to protect against the toxicity of venoms. Because bacteria represent a potent alternative source of toxins, we assessed the possible role of allergy-like type 2 immunity in antibacterial host defense. We discovered that the adaptive immune response against
Staphylococcus aureus
(SA) skin infection substantially improved systemic host defense against secondary SA infections in mice. Moreover, this acquired protection depended on IgE effector mechanisms and MCs. Importantly, our results reveal a previously unknown physiologic function of allergic immune responses, IgEs and MCs in host defense against a pathogenic bacterium.
The biological functions of IgE antibodies and mast cells, critical components of allergic diseases, have been enigmatic. Starkl
et al
. here report a role for this
allergy module
of immunity in host defense against the bacterial pathogen
Staphylococcus aureus
.
In our article entitled “IgE effector mechanisms, in concert with mast cells, contribute to acquired host defense against Staphylococcus aureus”, the following incorrect statement appears in the STAR ...Methods section under the subheading “Mass Spectrometry Data Analysis”: “Searches were performed with full tryptic digestion against the human SwissProt database v2017.06 (20456 sequences and appended known contaminants) with up to two miscleavage sites.” The correct sentence should read: “Searches were performed with full tryptic digestion against the mouse SwissProt database v2017.12 (25293 sequences and appended known contaminants) with up to two miscleavage sites.” The authors apologize for any confusion that may have arisen as a result of this error.
The metalloproteases meprin α and meprin β are highly expressed in the healthy gut but significantly decreased in inflammatory bowel disease, implicating a protective role in mucosal homeostasis. In ...the colon, meprin α and meprin β form covalently linked heterodimers tethering meprin α to the plasma membrane, therefore presenting dual proteolytic activity in a unique enzyme complex. To unravel its function, we applied N-terminomics and identified galectin-3 as the major intestinal substrate for meprin α/β heterodimers. Galectin-3-deficient and meprin α/β double knockout mice show similar alterations in their microbiome in comparison to wild-type mice. We further demonstrate that meprin α/β heterodimers differentially process galectin-3 upon bacterial infection, in germ-free, conventionally housed (specific pathogen-free), or wildling mice, which in turn regulates the bacterial agglutination properties of galectin-3. Thus, the constitutive cleavage of galectin-3 by meprin α/β heterodimers may play a key role in colon host-microbiome homeostasis.
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